EP3260455B1 - Inhibiteurs sélectifs de pi3k delta - Google Patents

Inhibiteurs sélectifs de pi3k delta Download PDF

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Publication number
EP3260455B1
EP3260455B1 EP17181585.5A EP17181585A EP3260455B1 EP 3260455 B1 EP3260455 B1 EP 3260455B1 EP 17181585 A EP17181585 A EP 17181585A EP 3260455 B1 EP3260455 B1 EP 3260455B1
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Prior art keywords
compound
disease
cancer
fluoro
lymphoma
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EP3260455A1 (fr
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Swaroop Kumar Venkata Satya VAKKALANKA
Meyyappan Muthuppalaniappan
Dhanapalan Nagarathnam
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Rhizen Pharmaceuticals AG
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Rhizen Pharmaceuticals AG
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Priority to PL17181585T priority Critical patent/PL3260455T3/pl
Priority to SM20190334T priority patent/SMT201900334T1/it
Priority to SI201331473T priority patent/SI3260455T1/sl
Priority to RS20190687A priority patent/RS58793B1/sr
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Definitions

  • phosphatidylinositol 3-kinase also referred to as PI 3-kinase or PI3K
  • PI 3-kinase PI 3-kinase
  • the PI3K delta inhibitor is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one hydrochloride.
  • the PI3K delta inhibitor is (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1 - yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-chromen-4-one benzenesulfonate.
  • Yet another aspect of the disclosure is a method of treating, preventing, and/or inhibiting a PI3K protein kinase mediated disease, disorder or condition (such as cancer or other proliferative disease or disorder) in a patient by administering to the a patient an effective amount of at least one compound of the present invention.
  • a PI3K protein kinase mediated disease, disorder or condition such as cancer or other proliferative disease or disorder
  • Another aspect of the disclosure is a method of treating an immune system-related disease (e.g., an autoimmune disease), a disease or disorder involving inflammation (e.g., asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, inflammatory bowel disease, glomerulonephritis, neuroinflammatory diseases, multiple sclerosis, uveitis and disorders of the immune system), cancer or other proliferative disease, a hepatic disease or disorder, or a renal disease or disorder.
  • the method includes administering an effective amount of one or more compounds of the present invention.
  • immune disorders which can be treated by the compounds of the present invention include, but are not limited to, psoriasis, rheumatoid arthritis, vasculitis, inflammatory bowel disease, dermatitis, osteoarthritis, asthma, inflammatory muscle disease, allergic rhinitis, vaginitis, interstitial cystitis, scleroderma, osteoporosis, eczema, allogeneic or xenogeneic transplantation (organ, bone marrow, stem cells and other cells and tissues) graft rejection, graft-versus-host disease, lupus erythematosus, inflammatory disease, type I diabetes, idiopathic pulmonary fibrosis (IPF) (or cryptogenic fibrosing alveolitis (CFA) or idiopathic fibrosing interstitial pneumonia), pulmonary fibrosis, dermatomyositis, Sjogren's syndrome, thyroiditis (e.g., Hashimoto's,
  • prodrugs can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product.
  • the prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life.
  • prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, amino acids, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound.
  • High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound.
  • Prodrugs of compounds A1, B, B1 and B2 are intended to be covered within the scope of this disclosure.
  • Salts may include acid addition salts where appropriate which are sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, methanesulphonates, benzoates, salicylates, benzenesulfonates, ascorbates, glycerophosphates, and ketoglutarates.
  • the salt is 4-methylbenzenesulfonate.
  • the salt is sulphate.
  • the salt is hydrochloride.
  • the salt is benzenesulfonate.
  • the salt is maleate.
  • the salt is camphor sulfonate.
  • cell proliferation refers to a phenomenon by which the cell number has changed as a result of division. This term also encompasses cell growth by which the cell morphology has changed (e.g., increased in size) consistent with a proliferative signal.
  • Autoimmune disease refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
  • the invention provides a pharmaceutical composition comprising one or more compounds of the present invention and one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutical composition includes a therapeutically effective amount of a compound of the present invention.
  • the pharmaceutical composition may include one or more additional active ingredients as described herein.
  • the amount of the compound to be administered is dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, preferably about 0.05 to about 2.5 g/day.
  • An effective amount of a compound of the invention may be administered in either single or multiple doses (e.g., twice or three times a day).
  • disorders, diseases, or conditions treatable with a compound provided herein include, but are not limited to,
  • Benzenesulphonic acid Compound B1 (1 eq.) dissolved in IPA, refluxed for 30min., acid(1.1eq.) in IPA was added, the clear solution not obtained, the residue was evaporated completely and was washed with water. 170-172 Maleic acid Compound B1 (1 eq.) dissolved in IPA, refluxed for 30min., acid (1.1eq.) in IPA was added, the clear solution not obtained, the residue was evaporated completely and was washed with water.
  • Assay 1 Fluorescent determination of PI3K enzyme activity
  • Growth inhibition assays were carried out using 10% FBS supplemented media. Cells were seeded at a concentration of 5000 - 20,000 cells/well in a 96-well plate. Test compound at a concentration range of from 0.01 to 10000 nM were added after 24 hours. Growth was assessed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) dye reduction test at 0 h (prior to the addition of the test compound) and 48 h after the addition of test compound. Absorbance was read on a Fluostar Optima (BMG Labtech, Germany) at a wave length of 450 nm. Data were analysed using GraphPad Prism and percent inhibition due to the test compound compared to the control was calculated accordingly.
  • MTT 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
  • Apoptosis in leukemic cells was determined using an in situ Caspase 3 kit (Millipore, US) as outlined below:
  • Assay 6a Screening for anticancer activity in Human Multiple Myeloma cells
  • Assay 7 Screening for anticancer activity in various leukemic cell line

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Claims (17)

  1. Composé choisi parmi la (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one et les sels pharmaceutiquement acceptables de celle-ci ayant un excès énantiomérique (e.e.) d'au moins environ 60 %, 75 %, 80 %, 85 %, 90 %, 95 %, 98 % ou 99 %.
  2. Composé selon la revendication 1, dans lequel le composé est le 4-méthylbenzènesulfonate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one.
  3. Composé selon la revendication 1, dans lequel le composé est choisi parmi :
    le sulfate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one ;
    le chlorhydrate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one ;
    le benzènesulfonate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one ;
    le maléate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one ; et
    le camphre sulfonate de (S)-2-(1-(4-amino-3-(3-fluoro-4-isopropoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)éthyl)-6-fluoro-3-(3-fluorophényl)-4H-chromén-4-one.
  4. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 60 %.
  5. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 75 %.
  6. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 80 %.
  7. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 85 %.
  8. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 90 %.
  9. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 95 %.
  10. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 98 %.
  11. Composé selon la revendication 2, ayant un excès énantiomérique (e.e.) d'au moins environ 99 %.
  12. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 11 et au moins un support pharmaceutiquement acceptable.
  13. Composé selon l'une quelconque des revendications 1 à 11 pour une utilisation dans une méthode d'inhibition d'une activité catalytique d'une PI3K kinase présente dans une cellule, dans lequel l'inhibition a lieu dans un sujet souffrant d'une maladie ou d'un trouble qui est le cancer, un trouble osseux, une maladie inflammatoire, une maladie immunitaire, une maladie du système nerveux, une maladie métabolique, une maladie respiratoire, la thrombose ou une maladie cardiaque.
  14. Composé selon l'une quelconque des revendications 1 à 11 pour une utilisation dans le traitement d'une maladie ou d'un trouble dans un sujet en ayant besoin, dans lequel la maladie, le trouble et l'état est une maladie se rapportant au système immunitaire, une maladie ou un trouble mettant en jeu une inflammation, un cancer ou autre maladie proliférative, une maladie ou un trouble hépatique ou une maladie ou un trouble rénal.
  15. Composé pour une utilisation selon la revendication 14, dans lequel la maladie, le trouble ou l'état est choisi parmi l'inflammation, la glomérulonéphrite, l'uvéite, les maladies ou troubles hépatiques, les maladies ou troubles rénaux, la maladie pulmonaire obstructive chronique, la polyarthrite rhumatoïde, la maladie inflammatoire de l'intestin, la vascularite, la dermatite, l'ostéoarthrite, la maladie musculaire inflammatoire, la rhinite allergique, la vaginite, la cystite interstitielle, la sclérodermie, l'ostéoporose, l'eczéma, la transplantation allogénique ou xénogénique, le rejet de greffe, la maladie du greffon contre l'hôte, le lupus érythémateux, la fibrose pulmonaire, la dermatomyosite, la thyroïdite, la myasthénie grave, l'anémie hémolytique auto-immune, la fibrose kystique, l'hépatite récidivante chronique, la cirrhose biliaire primaire, la conjonctivite allergique, l'hépatite, la dermatite atopique, l'asthme, le syndrome de Sjogren, le rejet de transplantation d'organe, la sclérose en plaques, Guillain-Barré, l'uvéite auto-immune, l'anémie hémolytique auto-immune, l'anémie pernicieuse, la thrombocytopénie auto-immune, l'artérite temporale, le syndrome des anti-phospholipides, les vascularites telles que la granulomatose de Wegener, la maladie de Behçet, le psoriasis, la dermatite herpétiforme, le pemphigus vulgaire, le vitiligo, la maladie de Crohn, la colite, la colite ulcéreuse, la cirrhose biliaire primaire, l'hépatite auto-immune, le diabète sucré de type 1 ou à médiation immune, la maladie de Grave, la thyroïdite de Hashimoto, l'oophorite et l'orchite auto-immunes, le trouble auto-immun de la glande surrénale, le lupus erythémateux systémique, la polymyosite, la dermatomyosite, la spondylarthrite ankylosante, le rejet de greffe, le rejet de greffe sur la peau, l'arthrite, les maladies osseuses associées avec une résorption osseuse accrue, l'iléite, le syndrome de Barrett, le syndrome de détresse respiratoire de l'adulte, la maladie pulmonaire obstructive chronique ; la dystrophie cornéenne, le trachome, l'onchocerc ose, l'ophtalmite sympathique, l'endophtalmie ; la gingivite, la périodontite ; la tuberculose, la lèpre, les complications urémiques, la névrose ; la sclérodermatite, le psoriasis, les maladies démyélinisantes chroniques du système nerveux, la neurodégénérescence associée au SIDA, la maladie d'Alzheimer, la méningite infectieuse, l'encéphalomyélite, la maladie de Parkinson, la maladie de Huntington, la sclérose latérale amyotrophique, l'encéphalite virale ou auto-immune ; les troubles auto-immuns, la vasculite à complexes immuns, le lupus systémique et l'érythématode ; le lupus érythémateux systémique (SLE) ; la cardiomyopathie, la maladie cardiaque ischémique, l'hypercholestérolémie, l'athérosclérose, la pré-éclampsie ; l'insuffisance hépatique chronique, le traumatisme du cerveau et de la moelle épinière, le cancer, les tumeurs hématopoïétiques de la lignée lymphoïde, la leucémie, la leucémie lymphoïde aigüe, la leucémie lymphoblastique aigüe, le lymphome à cellules B, le lymphome à cellules T, le lymphome de Hodgkin, le lymphome non hodgkinien, le lymphome à tricholeucocytes, et le lymphome de Burkett ; les tumeurs hématopoïétiques de la lignée myéloïde, la leucémie myéloïde aigüe, la leucémie myéloïde chronique, le syndrome myélodysplasique, la leucémie promyélocytaire ; le carcinome de la vessie, le carcinome du sein, le carcinome du côlon, le carcinome du rein, le carcinome du foie, le carcinome du poumon, le cancer du poumon à petites cellules, le cancer oesophagien, le cancer de la vésicule, le cancer ovarien, le cancer pancréatique, le cancer de l'estomac, le cancer du col de l'utérus, le cancer de la thyroïde, le cancer de la prostate, le cancer de la peau, le carcinome des cellules squameuses ; les tumeurs d'origine mésenchymateuse, le fibrosarcome, le rhabdomyosarcome ; les tumeurs du système nerveux central et périphérique, l'astrocytome, le neuroblastome, le gliome, le schwannome ; le mélanome, le séminome, le tératocarcinome, l'ostéosarcome, le xenoderma pigmentosum, le kératoacanthome, le cancer folliculaire de la thyroïde, le sarcome de Kaposi, la bronchite chronique, la leucémie lymphoïde chronique, les myélomes multiples qui comprennent le myélome multiple latent, le myélome non sécrétant, le myélome ostéosclérosant, la leucémie à plasmocytes, le plasmacytome solitaire et le plasmacytome extra-médullaire, le lymphome lymphocytaire à petits lymphocytes (SLL), le lymphome non hodgkinien indolent (I-NHL), le lymphome à cellules du manteau (MCL), le lymphome folliculaire, la macroglobulinémie de Waldeström (WM) et le lymphome diffus à grandes cellules B (DLBCL).
  16. Composé pour une utilisation selon la revendication 14, dans lequel la maladie, le trouble ou l'état est choisi parmi la leucémie lymphoïde chronique (CLL), le lymphome non hodgkinien (NHL), la leucémie myéloïde aiguë (AML), le myélome multiple (MM), le petit lymphome lymphocytaire à petits lymphocytes (SLL), le lymphome non Hodgkinien indolent (I-NHL), la leucémie lymphoïde aiguë (ALL), le lymphome à cellules du manteau (MCL), le lymphome folliculaire, la macroglobulinémie de Waldestrom (WM), le lymphome à cellules T, le lymphome à cellules B et le lymphome diffus à grandes cellules B (DLBCL).
  17. Composé pour une utilisation selon l'une quelconque des revendications 13 à 16, comprenant en outre au moins un autre agent anti-cancer, agent anti-inflammatoire, agent immunosuppresseur, stéroïde, agent anti-inflammatoire non stéroïdien, antihistaminique, analgésique ou un mélange de ceux-ci.
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